Tamcool Plus

Uses

• Anaphylaxis, asthma, severe hypersensitivity reactions
• Rheumatoid arthritis, juvenile chronic arthritis, polymyalgia rheumatica
• Systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease (other than systemic sclerosis), polyarteritis nodosa, sarcoidosis
• Pemphigus, bullous pemphigoid, pyoderma gangrenosum
• Minimal change nephrotic syndrome, acute interstitial nephritis
• Rheumatic carditis
• Ulcerative colitis, Crohn's disease
• Uveitis, optic neuritis
• Autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura
• Acute and lymphatic leukaemia, malignant lymphoma, multiple myeloma
• Immune suppression in transplantation

Tamsulosin Hydrochloride is used for the treatment of the signs and symptoms of Benign Prostatic Hyperplasia (BPH).

Tamcool Plus is also used to associated treatment for these conditions: Duchenne's Muscular Dystrophy (DMD)Benign Prostatic Hyperplasia (BPH), Benign Prostatic Hypertrophy, Bladder Outlet Obstruction, Ureteral Calculus

How Tamcool Plus works

Deflazacort is a corticosteroid prodrug with an active metabolite, 21-deflazacort, which binds to the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects on the body. The exact mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown but likely occurs via its anti-inflammatory activities.

Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas.

Dosage

Tamcool Plus dosage

Adults:

• For acute disorders:up to 120 mg/day Deflazacort may need to be given initially. Maintenance doses in most conditions are within the range 3-18 mg/day.
• Rheumatoid arthritis: The maintenance dose is usually within the range 3-18 mg/day. The smallest effective dose should be used and increased if necessary.
• Bronchial asthma: In the treatment of an acute attack, high doses of 48-72 mg/day may be needed depending on severity and gradually reduced once the attack has been controlled. For maintenance in chronic asthma, doses should be titrated to the lowest dose that controls symptoms.
• Other conditions: The dose of Deflazacort depends on clinical need titrated to the lowest effective dose for maintenance. Starting doses may be estimated on the basis of ratio of 5 mg prednisone or prednisolone to 6 mg Deflazacort.

Children:

Alternate day administration may be appropriate. Doses of Deflazacort usually lie in the range 0.25-1.5 mg/kg/day. The following ranges provide general guidance:

• Juvenile chronic arthritis: The usual maintenance dose is between 0.25 to 1.0 mg/kg/day.
• Nephrotic syndrome: Initial dose of usually 1.5 mg/kg/day followed by down titration according to clinical need.
• Bronchial asthma: The initial dose should be between 0.25 - 1.0 mg/kg on alternate days.
• Deflazacort withdrawal:In patients who have received more than physiological doses of systemic corticosteroids (approximately 9 mg per day or equivalent) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced.

The recommended dose of Tamsulosinis 0.4 mg once daily. It should be administered approximately half/hour following the same meal each day. For those patients who fail to respond to the 0.4 mg dose after two to four weeks of dosing, the dose of Tamsulosin can be increased to 0.8mg once daily. If Tamsulosin administration is discontinued or interrupted for several days at either the 0.4 mg or 0.8 mg dose, therapy should be started again with the 0.4 mg once daily dose.

Side Effects

After administration occasionally GI disturbances like dyspepsia, nausea; musculoskeletal disorders like myopathy; depressed mood, skin atrophy, acne etc. may occur.

The following adverse reactions have been reported during the use of Tamsulosin: dizziness, abnormal ejaculation, and less frequently (1-2%) headache, asthenia, postural hypotension, palpitations, and rhinitis.

Gastrointestinal reactions such as nausea, vomiting, diarrhoea, and constipation can occasionally occur. Hypersensitivity reactions such as rash, pruritus, and urticaria can occur occasionally. As with other alpha-blockers, drowsiness, blurred vision, dry mouth, or edema can occur. Syncope has been reported rarely, and there have been very rare reports of angioedema and priapism.

Toxicity

The LD50 for the oral dose is 5200 mg/kg (mouse); Oral TDLO (woman): 0.12 mg/kg

A note on altered endocrine function and immunosuppression

Deflazacort, as a steroid prodrug used over a long-term period, can cause hormone imbalance leading to diseases such as Cushing's Syndrome and hypothalamic-pituitary-adrenal axis suppression. It can also predispose to infection, as it promotes immunosuppression. It is important to monitor for hormonal imbalance and infection and provide necessary treatment if they occur.

Mutagenicity/carcinogenicity

Mutagenicity assays were negative in various laboratory and in vivo assays performed on rats. Chronic use in mice for 2 years in one study resulted in a higher rate of osteoma and osteosarcomas in mice receiving 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg of deflazacort daily.

Use in pregnancy

There are no sufficient data to support the administration of deflazacort during pregnancy. Corticosteroid drugs such as deflazacort should only be used during pregnancy only if the benefits of therapy outweigh the potential risks.

Use in lactation

Corticosteroids, when administered systemically, are excreted in the breastmilk. Exposure may lead to disturbances in bone development and growth and endocrine disturbances in the exposed infant.

In the event of overdose, patients may experience hypotension and should lie down in a supine position to maintain blood pressure and heart rate. If further measures are required intravenous fluids should be considered. If further progression is required, vasopressors may be used and renal function should be monitored. Dialysis is unlikely to assist in treating overdose because tamsulosin is extensively protein bound.

The oral LD50 in rats is 650mg/kg.

Tamsulosin is not indicated for use in women and no studies have been performed in pregnancy, though animal studies have not shown fetal harm. Tamsulosin is excreted in the milk of rats but there is no available data on what the effect of this tamsulosin exposure may be. Animal studies have shown male and female rat fertility is affected by tamsulosin due to impairment of ejaculation and fertilization. In men, tamsulosin is associated with abnormal ejaculation. Tamsulosin is not mutagenic but may be carcinogenic at levels above the maximum recommended human dose. Female rats experience a slight increase in the rates of mammary gland fibroadenomas and adenocarcinomas.

Precaution

The following clinical conditions require special caution and frequent patient monitoring is necessary: Adrenal suppression and infection, child, adolescents, elderly, history of TB and steroid myopathy, hypertension, recent myocardial infarction, congestive heart failure, liver failure, renal impairment, diabetes mellitus and glaucoma (including family history), osteoporosis, corneal perforation, epilepsy, peptic ulcer, hypothyroidism, pregnancy and lactation.

Not indicated for use in women. Severe renal impairment (CrCl <10 mL/min). Pregnancy and lactation.

Interaction

Deflazacort is metabolized in the liver. It is recommended to increase the maintenance dose of Deflazacort if drugs which are liver enzyme inducers are co-administered, e.g. rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide. For drugs which inhibit liver enzymes, (e.g. ketoconazole) it may be possible to reduce the maintenance dose of Deflazacort.

Increased plasma concentration with strong CYP3A4 inhibitors (e.g. ketoconazole). Moderate CYP3A4 inhibitors (e.g. erythromycin), strong (e.g. paroxetine) or moderate (e.g. terbinafine) CYP2D6 inhibitors may increase exposure of tamsulosin. Increased plasma concentration with cimetidine. Additive effect with other α-adrenergic blocking agents. Concomitant use with PDE5 inhibitors may lead to symptomatic hypotension. Decreased plasma concentration with furosemide.

Volume of Distribution

One study determined the volume of distribution to be 204 ± 84 L.

16L after intravenous administration.

Elimination Route

Deflazacort is rapidly absorbed after oral administration with peak concentration occurring within 1-2 hours. One pharmacokinetic study determined an AUC (area under the curve) of 280 ng/ml · h.

The bioavailability of both the oral suspension and tablet are similar. In clinical studies, coadministration of deflazacort crushed with food or applesauce did not affect absorption or bioavailability.

Oral tamsulosin is 90% absorbed in fasted patients. The area under the curve is 151-199ng/mL*hr for a 0.4mg oral dose and 440-557ng/mL*hr for a 0.8mg oral dose. The maximum plasma concentration is 3.1-5.3ng/mL for a 0.4mg oral dose and 2.5-3.6ng/mL for a 0.8mg oral dose. Taking tamsulosin with food increases the time to maximum concentration from 4-5 hours to 6-7 hours but increases bioavailability by 30% and maximum plasma concentration by 40-70%.

Half Life

The half-life of deflazacort ranges from 1.1 to 1.9 h

The half life in fasted patients is 14.9±3.9 hours. The elimination half life is 5-7 hours and the apparent half life is 9 to 13 hours in healthy subjects. In patients who require tamsulosin, the apparent half life is 14-15 hours.

Clearance

114 ±27 L/h, according to one noncompartmental pharmacokinetic study.

The clearance of corticosteroids is enhanced in hypothyroid patients and increased in patients with hyperthyroidism. Dosing adjustments may be considered according to thyroid status. A study of corticosteroid clearance was performed in patients with a creatinine clearance of 15 mL/min or less, and determined that the active metabolite of deflazacort, 21-deflazacort was similar to that in patients with normal renal clearance.

2.88L/h.

Elimination Route

Urinary excretion is the major route of deflazacort elimination, accounting for about about 70% of the excreted dose. The remainder of the dose (about 30%) is excreted in the feces. Elimination is almost completed by 24 hours post-dose. 21-deflazacort makes up about 18% of the eliminated drug in the urine.

97% of an orally administered does is recovered in studies, which 76% in the urine and 21% in the feces after 168 hours. 8.7% of the dose is excreted as unmetabolized tamsulosin.

Pregnancy & Breastfeeding use

Use in pregnancy: Deflazacort does cross the placenta. When administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks.

Use in lactation: Corticosteroids are excreted in breast milk. Doses up to 50 mg daily of Deflazacort are unlikely to cause systemic effects in the infant.

Tamsulosin Hydrochloride capsules are not indicated for use in women.

Contraindication

Hypersensitivity to or any of the ingredients. Patients receiving live virus immunisation.

History of orthostatic hypotension. Severe hepatic impairment.

Special Warning

Elderly: In elderly patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

Hepatic impairment: In patients with hepatic impairment, blood levels of Deflazacort may be increased. Therefore the dose of Deflazacort should be carefully monitored and adjusted to the minimum effective dose.

Renal impairment: In renal impaired patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

Tamsulosin Hydrochloride capsules are not indicated for use in pediatric populations.

Acute Overdose

In patients who have received more than physiological doses of systemic corticosteroids (approximately 9mg per day or equivalent) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should becarried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced.

As overdose of Tamsulosin Hydrochloride capsules lead to hypotension, support the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in supine position. If this measure is inadequate, then administration of intravenous fuid should be considered. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

Storage Condition

Store in a cool (below 25° C.) and dry place , protected from light & moisture. Keep out of the reach of children.

Store between 20-25° C.

Innovators Monograph

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